Investigating the impact of EBS-causing mutations on epigenetic gene regulation (Connelly 1)Ongoing
|Project lead||Prof John Connelly|
|Organisation||Queen Mary University of London, Centre for Cell Biology and Cutaneous Research, London, UK|
|Project budget||GBP 33,589.00|
|Start date / Duration||01. Apr 2023 / 9 months|
|Funder(s) / Co-Funder(s)||DEBRA Austria|
|Research area||EB genetics, epigenetics & biology|
Publications related to the projectsThe keratin network of intermediate filaments regulates keratinocyte rigidity sensing and nuclear mechanotransduction
Short lay summary
Epidermolysis bullosa simplex (EBS) is a severe blistering skin disease caused by mutations in keratins that are essential for skin strength and resiliency. Recent studies by our team have discovered that keratin defects also cause dramatic changes in the structural properties of the nucleus of skin cells. As the nucleus is a central point for regulating gene expression, we hypothesise that these structural changes in the nucleus also influence the organisation of DNA (also known as the epigenetic state) and expression of genes. The proposed project will therefore investigate how EBS mutations influence the cell’s epigenetic state. We will profile the global changes in key epigenetic markers in healthy and patient-derived keratinocytes and skin samples. The findings will provide new and fundamental insights into EBS pathology, specifically the epigenetic state, which is a powerful regulator of cell function but currently unknown in EBS.
Epidermolysis bullosa simplex (EBS) is a severe blistering skin disease caused by structural defects in the keratin cytoskeleton, and our recent studies have identified further alterations in nuclear architecture due to keratin instability. However, the impact of these changes on nuclear mechanics, chromatin structure, and epigenetic gene regulation have yet to be determined, thereby limiting further investigation into epigenetic mechanisms involved in disease pathogenesis and the development of novel disease modifying therapies. The aim of this project is to explore the potential epigenetic changes in chromatin remodelling associated with EBS. Here, we will perform global analysis of specific histone modifications in patient-derived keratinocytes and compare these to the patterns of expression in keratinocytes from healthy donors. In addition, we will confirm key changes by immunofluorescence staining of normal and EBS skin samples. These studies will provide fundamental insights into the epigenetic landscape of EBS and generate essential proof-of-principle data to support future mechanistic investigations into disease pathogenesis and identification of novel therapeutic targets.
This line of research has the potential to uncover new strategies for modifying disease severity. If the epigenetic state is altered in EBS cells and influences disease severity, it may be possible to dampen unwanted symptoms or enhance healing responses through the use of drugs that target DNA organisation and structure (e.g. epigenetic inhibitors). This could be an attractive therapeutic approach because it could modify whole programmes of gene expression, and recent studies by our group and others have demonstrated beneficial effects of epigenetic inhibitors on wound healing responses. However, fundamental research carried out in this project and future studies will first be essential to advance these types of therapies.